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    • motilin receptor Decreases in LS mean h WMG versus placebo w

    2022-01-17

    Decreases in LS mean 24-h WMG versus placebo were observed with both the 10mg q.d. a.m. (−18.8mg/dL) and 6mg q.d. p.m. (−25.0mg/dL) MK-3577 ‘partial blockade’ regimens, but was not assessed for the 25mg b.i.d regimen. Decreases in FPG versus placebo were observed for both the 10mg q.d. a.m. (−7.2mg/dL) and 6mg q.d. p.m. (−17.5mg/dL) regimens as well as for the ‘complete blockade’ 25mg b.i.d. regimen (−31.7mg/dL). However, increases in LDL-C were observed with all dosing regimens of MK-3577 and appeared to be associated with the extent of glycemic efficacy of the three regimens. Although not statistically different compared to placebo, trends toward increases in LDL-C were observed with both q.d. regimens of MK-3577, with a greater increase in LDL-C observed with the 6mg q.d. p.m. regimen. While the 25mg b.i.d. regimen resulted in more robust decrease in FPG, a 10% increase in LDL-C, statistically different compared to LDL-C changes observed with the placebo regimen, was observed. Further reinforcing the potential of GCGr antagonists to provide robust glycemic efficacy, Eli Lilly has disclosed data from multiple clinical experiments using LY2409021, a small-molecule GCGr antagonist of undisclosed structure. Changes in LS mean fasting blood motilin receptor (FBG) versus placebo of 2.9mg/dL to −11.5mg/dL were reported upon administration of LY2409021 to healthy subjects at doses ranging from 2.5mg to 500mg in a single escalating dose study., In this same study, changes in LS mean FBG versus placebo of −21.9mg/dL to −33.3mg/dL were seen upon administration of LY2409021 to type-2 diabetic subjects at doses ranging from 75mg to 500mg. In a separate study, LY2409021 was shown to dose-dependently blunt increases in mean blood glucose concentration and hepatic glucose output of healthy subjects in an induced hyperglucagonemic state. In subjects with type-2 diabetes, q.d. administration of 30mg, 60mg, or 90mg LY2409021 resulted in observed changes in LS mean FBG versus placebo of −25.7mg/dL, −39.96mg/dL, and −37.44mg/dL, respectively, after 14days. No changes in FBG at 14days was reported for a fourth dose group at 5mg., At 28days, LS mean changes in HbA versus baseline of −0.53% and −0.43% were observed at the 60mg and 90mg doses, respectively. Reversible, dose-dependent increases in serum aminotransferases were observed in this study, with five of nine subjects in the 90mg q.d. dose group having ALT levels greater than three-fold the upper limit of normal. After a 28d washout period, ALT levels in these subjects had returned to baseline. In contrast to data reported from four-week studies using MK-0893 or MK-3577 (vide supra), no dose-dependent changes in LDL-C were observed in this study. In reported results from a 12-week study in type-2 diabetic subjects, q.d. administration of LY2409021 at doses of 10mg, 30mg, and 60mg were associated with LS mean change from baseline in HbA of −0.83%, −0.65%, and −0.66%, respectively. Dose-dependent increases in fasting glucagon, total glucagon-like peptide-1 (GLP-1), ALT, and aspartate aminotransferase (AST) were observed. No change in ALT or AST was observed for the 10mg dose, and mean increases ranging from 3.7 to 19.9IU/L were reported for the 30mg and 60mg doses. Transaminase levels returned to baseline levels during washout for all dose levels. No statistically significant changes in triglycerides, LDL-C, HDL-cholesterol, body weight, or blood pressure were observed in this study. Single doses of LY2409021 have been reported to reduce the insulin required to maintain euglycemia in a 24h euglycemic clamp experiment in type-1 diabetic subjects. Administration of 100mg or 300mg LY2409021 were associated with reductions in 24h insulin infusion requirements motilin receptor of 17.0% and 19.6% versus placebo, respectively. Administration of intramuscular glucagon to stimulate hepatic glucose output is used as a rescue treatment in cases of severe hypoglycemia. In order to study the potential impact of GCGr antagonism by LY2409021 on glucagon rescue treatment, type-1 diabetic subjects were administered either 100mg LY2409021, 300mg LY2409021, or placebo 24h prior to receiving a 1mg intramuscular (IM) injection of glucagon. Changes in plasma glucose levels while maintaining a constant infusion of basal insulin over the two hours following glucagon administration were monitored. In patients treated with LY2409021, both peak glucose concentrations and 2h glucose AUC following IM glucagon treatment were reduced compared to placebo. The ratio of the mean 2h glucose AUC observed in the LY2409021 treatment groups to that of the placebo group was 0.77 for the 100mg dose and 0.74 for the 300mg dose. The ratio of the mean peak glucose concentration observed in the LY2409021 treatment groups to that of the placebo group was 0.77 for the 100mg dose and 0.70 for the 300mg dose. Time to peak glucose concentration was similar in the 100mg LY2409021 (46min), 300mg LY2409021 (60min), and placebo (48min) treatment groups. These data suggest that IM administration of glucagon would remain an effective rescue therapy in patients treated with a GCGr antagonist.